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Title: | Mutations in RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia |
Author: | Giménez Carabaza, Neus Martínez Trillos, Alejandra Montraveta, Arnau López-Guerra, Mónica Rosich, Laia Nadeu, Ferran Valero, Juan G. Aymerich Gregorio, Marta Magnano, Laura Rozman, María Matutes, Estella Delgado, Julio (Delgado González) Baumann, Tycho Gine, Eva González, Marcos Alcoceba, Miguel Terol, Maria José Navarro, Blanca Colado, Enrique Payer, Ángel R. Puente, Xose S. López-Otin, Carlos López Guillermo, Armando Campo Güerri, Elias Colomer Pujol, Dolors Villamor i Casas, Neus |
Keywords: | Leucèmia limfocítica crònica Mutació (Biologia) Chronic lymphocytic leukemia Mutation (Biology) |
Issue Date: | Mar-2019 |
Publisher: | Ferrata Storti Foundation |
Abstract: | Mutations in genes of the RAS-BRAF-MAPK-ERK pathwayhave not been fully explored in patients with chronic lym-phocytic leukemia. We, therefore, analyzed the clinical andbiological characteristics of chronic lymphocytic leukemia patientswith mutations in this pathway and investigated thein vitroresponseof primary cells to BRAF and ERK inhibitors. Putative damaging muta-tions were found in 25 of 452 patients (5.5%). Among these, BRAFwas mutated in nine patients (2.0%), genes upstream of BRAF(KITLG,KIT, PTPN11, GNB1, KRASand NRAS) were mutated in 12 patients(2.6%), and genes downstream of BRAF(MAPK2K1, MAPK2K2, andMAPK1) were mutated in five patients (1.1%). The most frequentmutations were missense, subclonal and mutually exclusive. Patientswith these mutations more frequently had increased lactate dehydro-genase levels, high expression of ZAP-70, CD49d, CD38, trisomy 12and unmutated immunoglobulin heavy-chain variable region genesand had a worse 5-year time to first treatment (hazard ratio 1.8,P=0.025). Gene expression analysis showed upregulation of genes ofthe MAPK pathway in the group carrying RAS-BRAF-MAPK-ERKpathway mutations. The BRAF inhibitors vemurafenib and dabrafenibwere not able to inhibit phosphorylation of ERK, the downstreameffector of the pathway, in primary cells. In contrast, ulixertinib, apan-ERK inhibitor, decreased phospho-ERK levels. In conclusion,although larger series of patients are needed to corroborate these find-ings, our results suggest that the RAS-BRAF-MAPK-ERK pathway isone of the core cellular processes affected by novel mutations inchronic lymphocytic leukemia, is associated with adverse clinical fea-tures and could be pharmacologically inhibited. |
Note: | Reproducció del document publicat a: https://doi.org/10.3324/haematol.2018.196931 |
It is part of: | Haematologica, 2019, vol. 104, num. 3, p. 576-586 |
URI: | http://hdl.handle.net/2445/148047 |
Related resource: | https://doi.org/10.3324/haematol.2018.196931 |
ISSN: | 0390-6078 |
Appears in Collections: | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) Articles publicats en revistes (Fonaments Clínics) |
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